Description of Itmat Expertise

Description of Other Expertise

In my capacity as Director of Epilepsy Research and Translational Neuroscience, as well as the natural extension of my own translational research, I have become involved in clinical research projects.
1) FDA- approved Phase I/II trial of bumetanide in neonatal seizures. I serve as FDA sponsor, and this project has emerged directly from basic research performed in my laboratory as well as Dr. Kevin Staley, and others. The trial was funded by an NIH RO1 grant (2010-2015), with the PI being Dr. Janet Soul, and Drs. Jensen and Staley are among the Co-PIs. The trial is now actively recruiting patients
2) Examination of cognitive and psychological comorbidities in pediatric epilepsies. In a first study, a team of from the Psychiatry department (J Gonzalez, MD and K Boyer, PhD) and Neurology (M Takeoka, MD) are examing the incidence of depression and learning disabilities in children with complex partial seizures and childhood absence epilepsy. In a related study, we are examining the incidence of learning disabilities in benign rolandic epilepsy in children, and the extent to it is related to the frequency of ictal and interictal EEG abnormalities.
3) Examination of abnormal synaptic transmission in human tissue removed from patients with refractory epilepsy or encephalitis. This is an interdisciplinary group and investigative only but has developed a centralized multi-PI IRB with universal consent form to improve availability of human tissue for experimental study and genetics.

Description of Research Expertise

The primary focus of my research is to investigate pathophysiological mechanisms of epilepsy and stroke, and secondary effects on synaptic plasticity. A secondary goal is to elucidate age-dependent differences in such mechanisms, and to examine the interactions between brain development, excitotoxic brain injury, epilepsy and cognition. Neurotransmitter receptors are developmentally regulated, and we have specifically demonstrated critical roles of these receptors, as well as their upstream modulators and downstream effectors, in neuronal and glial cells that are unique to the immature, implying age-specific disease mechanisms. The overall aim is to develop new targets based on novel mechanisms for the treatment of epilepsy, stroke, and autism.

Summary of major research findings:
1. Establishment of in vivo and in vitro rodent models of neonatal seizures and perinatal hypoxic/ischemic cerebral injury for examination of cellular and molecular factors influencing age-specific susceptibility, epileptogenicity, and cellular injury.
2. Demonstration that calcium-permeable AMPA receptors are constitutively expressed on neurons and glia in developing rodent and human hippocampus and neocortex, and that these are critical to the mechanisms of seizures and ischemic injury in the developing brain.
3. First demonstration that AMPA receptor antagonists selectively block seizures in the immature brain, but not in the adult. Additional demonstration that the clinically available drugs topiramate and talampanel attenuate AMPA receptor currents and suppress neonatal seizures and stroke, including periventricular leukomalacia, in rat models.
4. Elucidation of novel calcium-mediated signaling pathways downstream from the AMPA receptor that play critical roles in the pathogenesis of epilepsy in the immature brain, and preclinical efficacy of preventative or rescue treatment in rodent models. Specific pathways include those mediated by early post-translational changes to glutamate and GABA receptors that increase synaptic excitability. First demonstration that AMPA receptor antagonists including NBQX, topiramate and talampanel can reverse these changes when administered as post-seizure treatment, and prevent long term changes.
5. Identification of novel phosphorylation sites Ser 831 and Ser 845 on the GluR1 subunit of the AMPA receptor that are required for the epileptogenic effect of early life seizures, suggesting a novel mechanism for epileptogenesis.
6. Development of novel antiepileptic and neuroprotective strategies that are permissive of neuronal plasticity and long term potentiation. These include the NMDA receptor redox site modulator pyrroloquinoline quinone, and the use-dependent, uncompetitive NMDA blocker memantine as highly protective in vivo and in vitro stroke models, without significant neurocognitive effects.
7. Identified parallel patterns of relative underexpression of the KCC2 chloride transporter versus NKCC1 transporter in human and rodent perinatal cortex during developmental period when GABA receptor agonists are ineffective as antiepileptic agents. This result is the first to strongly implicate the presence of depolarizing GABA receptors in human neonates. This date provided the preclinical target validation that was critical for translation of the use of the NKCC1 inhibitor bumetanide in an FDA approved NIH-funded ongoing clinical trial at CHB and Partners – Phase I/II safety PK trial in neonatal seizures.
8. Elucidation of abnormal patterns of glutamate and GABA receptors,in human tissue from malformations of cortical development, such as Tuberous Sclerosis, and that these changes are associated with epileptic foci. These results are presently under evaluation with respect to the generation of new clinical treatment trials.
9. Demonstration of convergence of signaling deficits in early life seizures and autism. Alterations in canonical autism-related pathways, including mTOR, FMRP and MeCP2, occur secondary to seizures in the developing brain.

In summary, the emphasis of this translational research program is to identify age-specific mechanisms of brain injury at the cellular level using a variety of in vivo and in vitro techniques, and to use this information to explore and devise experimental therapeutic strategies with clinical potential. Several therapeutic strategies developed in the laboratory are being considered for clinical development. We have established IRBs that have created a repository of human tissue from surgical specimens and autopsy material, and routinely obtain brain tissue directly from surgery for electrophysiological investigation.